This proposal outlines an interdisciplinary collaboration between a group of senior clinical investigators who have experience in the design, recruitment, enrollment, and retention of persons with acute and early HIV infection, and a group of experienced basic science researchers who have expertise in the field of cellular immunology and the molecular virology of HIV. The proposal links the laboratories of Dr. James I. Mullins (University of Washington) with 5 collaborating clinical sites at the University of Washing, University of Minnesota, University of Geneva, University of New South Wales, and 7 of the 8 HIVNET Vaccine Preparedness sites. The core virological assays to document seroconversion and monitor the humoral and virological response in the proposed natural history and treatment studies will be performed in the laboratories of Dr. L. Corey (University of Washington), Dr. Luc Perrin (University of Geneva), and Dr. Haynes Sheppard (California State Health Department). The statistical and data management support will be directed by Dr. Steven Self of the Fred Hutchinson Cancer Research Center. The investigators involved in the study group have published over 70 articles in the area of primary HIV and all the investigators have ongoing collaborations with Dr. Corey the PI of the Study Group. We anticipate enrolling 45 patients with acute and 115 patients with early (defined as 150 days from acquisition of infection) yearly. The involvement of the HIVNET collaborating groups provides a population based sampling of patients with recently acquired HIV< especially those with subclinical infection. We will evaluate whether initial HIV-1 specific CD8 T cell responses as measured by TCR repertoire are predictive of subsequent disease progression, 2) ascertain if HIV specific envelope CTL induced in acute and early infection control viral load and influence outcome or whether changes in viral load are associated with alterations and recognition of epitopes expressed by autologous strains or with antagonisms by minimally altered viral epitopes, 3) determine whether selective pressures applied prior to detectable immune responses to the envelope gene are distinct and more stringently purifying than those applied to other regions of the viral genome, and 4) establish a clinical trials network to identify, enroll and retain patients with clinical and subclinical acute and early HIV infection and to conduct pilot phase I trials of novel antiviral therapy. Proposed treatment trials include 1) an evaluation of combination antiretroviral therapy on the tissue reservoirs of HIV-1 among those with acute and early HIV, 2) a pilot trial of reducing T cell activation with prednisone and concurrent antiretroviral therapy among persons with early HIV, and 3) a phase II study of triple versus double combination antiretroviral therapy for the treatment of early HIV.